Anticachectic composition

ABSTRACT

A medicinal composition for the prophylaxis and treatment of cachexia which comprises a compound of the formula: ##STR1## wherein R represents a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted; Y represents a group of the formula --CO--, --CH(OH)--, or --NR 3  -- (R 3  represents an alkyl group that may be substituted); m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q represents oxygen or sulfur; R 1  represents hydrogen or an alkyl group; ring E may have further 1 to 4 substituents, which may form a ring in combination with R 1  ; L and M respectively represent hydrogen or may be combined with each other to form a bond, provided that when m and n are 0, X represents CH, A represents a bond, Q represents sulfur, R 1 , L and M respectively represent hydrogen, and ring E does not have further substituents, R does not represent dihydrobenzopyranyl; or a salt thereof.

TECHNICAL FIELD

The present invention relates to a medicinal composition for theprophylaxis and treatment of cachexia which develops in chronic diseasessuch as malignant tumor, tuberculosis, diabetes, blood dyscrasia,endocrine disease, infectious disease, or acquired immunodeficiencysyndrome.

BACKGROUND ART

Cachexia is a systemic syndrome with progressive loss of body weight,anemia, edema, and anorexia as cardinal symptoms which develops inchronic diseases such as malignant tumor, tuberculosis, diabetes, blooddyscrasia, endocrine disease, infectious disease, and acquiredimmunodeficiency syndrome [e.g. Kern et al., Cancer Cachexia, J.Parenteral and Enteral Nutrition, 12, 286-298 (1988) and AmericanJournal of Medicine, 85, 289-291 (1988)].

In cachexia, therapeutic nutrition and endocrine therapy are generallyadministered but a satisfactory anticachectic modality remains to beestablished. Particularly where cachexia is caused by a malignant tumor,the available anticancer chemotherapy cannot be administered whencachexia is progressing, with the result that the treatment encounters aserious setback. Moreover, any therapeutic nutrition for relief ofcachectic symptoms may rather exacerbate the malignant tumor and detractfrom the life expectancy of the patient. While cachexia is frequentlycaused by the malignant tumors, administration of an antitumor agent insuch settings may result in control of the tumors but generally sideeffects of the drug develop in superimposition, the net result being noimprovement in cachexia [Nelson et al., Journal of Clinical Oncology,12, 213-225 (1994)].

In the above state of the art, there is a standing need for ananticachectic composition that should ameliorate or inhibit progressionof cachectic symptoms such as loss of body weight.

DISCLOSURE OF INVENTION

The present invention relates to a medicinal composition for theprophylaxis and treatment of cachexia which comprises a compound of theformula: ##STR2## wherein R represents a hydrocarbon group that may besubstituted or a heterocyclic group that may be substituted; Yrepresents a group of the formula --CO--, --CH(OH)--, or --NR³ -- (R³represents an alkyl group that may be substituted); m is 0 or 1; n is 0,1 or 2; X represents CH or N; A represents a bord or a bivalentaliphatic hydrocarbon group having 1 to 7 carbon atoms; Q representsoxygen or sulfur; R¹ represents hydrogen or an alkyl group; ring E mayhave further 1 to 4 substituents, which may form a ring in combinationwith R¹ ; L and M respectively represent hydrogen or may be combinedwith each other to form a bond; provided that when m and n are 0, Xrepresents CH, A represents a bond, Q represents sulfur, R¹, L and Mrespectively represent hydrogen, and ring E does not have furthersubstituents, R does not represent dihydrobenzopyranyl; or a saltthereof (hereinafter referred to simply as Compound (I)).

Referring to the hydrocarbon group that may be substituted for R, thehydrocarbon group includes aliphatic, alicyclic, alicyclic-aliphatic,aromatic-aliphatic, and aromatic hydrocarbon groups. The preferrednumber of carbon atoms constituting such hydrocarbon groups is 1 to 14.

The aliphatic hydrocarbon group is preferably a C₁₋₈ aliphatichydrocarbon group. The aliphatic hydrocarbon group includes saturatedC₁₋₈ aliphatic hydrocarbon groups (e.g. alkyl groups) such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, heptyl, and octyl; andunsaturated C₂₋₈ aliphatic hydrocarbon groups (e.g. alkenyl, alkadienyl,alkynyl, and alkadiynyl groups) such as ethenyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl,3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl,2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, and 1-octynyl.

The alicyclic hydrocarbon group is preferably a C₃₋₇ alicyclichydrocarbon group. The alicyclic hydrocarbon group includes saturatedC₃₋₇ alicyclic hydrocarbon groups (e.g. cycloalkyl groups) such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. andunsaturated C₅₋₇ alicyclic hydrocarbon groups (e.g. cycloalkenyl andcycloalkadienyl groups) such as 1-cyclopentenyl, 2-cyclopentenyl,3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, and2,4-cycloheptadienyl.

The alicyclic-aliphatic hydrocarbon group is a group consisting of theabove-described alicyclic hydrocarbon group and aliphatic hydrocarbongroup (e.g. cycloalkyl-alkyl and cycloalkenyl-alkyl groups) and ispreferably a C₄₋₉ alicyclic-aliphatic hydrocarbon group. Specifically,the alicyclic-aliphatic hydrocarbon group includes cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl,2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl,2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl,cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc.

The aromatic-aliphatic hydrocarbon group is preferably a C₇₋₁₃aromatic-aliphatic hydrocarbon group (e.g. aralkyl and arylalkenylgroups). The aromatic-aliphatic hydrocarbon group includes C₇₋₉phenylalkyl such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl,2-phenylpropyl and 1-phenylpropyl; C₁₁₋₁₃ naphthylalkyl such asα-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, andβ-naphthylethyl; C₈₋₁₀ phenylalkenyl such as styryl and4-phenyl-1,3-butadienyl; and C₁₂₋₁₃ naphthylalkenyl such as2-(2-naphthyl)vinyl.

The aromatic hydrocarbon group is preferably a C₆₋₁₄ aromatichydrocarbon group (e.g. aryl groups). The aromatic hydrocarbon groupincludes phenyl and naphthyl (α-naphthyl, β-naphthyl).

Referring to the formula (I), the heterocyclic group in a heterocyclicgroup that may be substituted for R is a 5- to 7-membered monocyclicheterocyclic group containing 1 to 4 hetero-atoms selected from oxygen,sulfur, and nitrogen in addition to carbon as ring members or acondensed heterocyclic ring group. The condensed heterocyclic ring mayfor example be one consisting of such a 5- to 7-membered monocyclicheterocyclic group and a 6-membered ring containing 1 or 2 nitrogenatoms, a benzene ring, or a 5-membered ring containing one sulfur atom.

Specifically the heterocyclic group includes 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,isothiazolyl, isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl,benzimidazol-2-yl, indol-3-yl, 1H-indazol-3-yl,1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,1H-imidazo[4,5-b]pyrazin-2-yl, and benzopyranyl. The preferredheterocyclic group is pyridyl, oxazolyl, or thiazolyl.

Referring to the formula (I), the hydrocarbon group and heterocyclicgroup for R may respectively have 1 to 5, preferably 1 to 3 substituentsat substitutable positions. Such substituents include for examplealiphatic hydrocarbon groups, alicyclic hydrocarbon groups, aryl groups,aromatic heterocyclic groups, nonaromatic heterocyclic groups, halogen,nitro, amino group that may be substituted, acyl groups that may besubstituted, hydroxy group that may be substituted, thiol that may besubstituted, and carboxyl group that may be esterified.

The aliphatic hydrocarbon group includes straight-chain or branchedaliphatic hydrocarbon groups having 1 to 15 carbon atoms, such as alkyl,alkenyl, and alkynyl groups.

The preferred alkyl group is a C_(1-1O) alkyl group, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,isopentyl, neo-pentyl, t-pentyl, 1-ethylpropyl, hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl,hexyl, pentyl, octyl, nonyl, and decyl.

The preferred alkenyl group is a C₂₋₁₀ alkenyl group, such as vinyl,allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

The preferred alkynyl group is a C₂₋₁₀ alkynyl group, such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, and 5-hexynyl.

The alicyclic hydrocarbon group includes saturated and unsaturatedalicyclic hydrocarbon groups having 3 to 12 carbon atoms, such ascycloalkyl, cycloalkenyl, and cycloalkadienyl groups.

The preferred cycloalkyl group is a C₃₋₁₀ cycloalkyl group, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,bicyclo[4.2.1]nonyl, and bicyclo[4.3.1]decyl.

The preferred cycloalkenyl group is a C₃₋₁₀ cycloalkenyl group, such as2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl.

The preferred cycloalkadienyl group is a C₄₋₁₀ cycloalkadienyl group,such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl.

The term "aryl group" means a monocyclic or condensed polycyclicaromatic hydrocarbon group. As preferred examples, C₆₋₁₄ aryl groupssuch as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl can bementioned. Particularly preferred are phenyl, 1-naphthyl, and2-naphthyl.

The preferred aromatic heterocyclic group includes 5- to 7-memberedmonocyclic aromatic heterocyclic groups containing 1 to 4 hetero-atomsselected from oxygen, sulfur, and nitrogen in addition to carbon as ringmembers, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, and triazinyl; and dicyclic or tricyclic condensed aromaticheterocyclic groups containing 1 to 5 hetero-atoms selected from oxygen,sulfur, and nitrogen in addition to carbon as ring members, such asbenzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl,1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl,benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, and 1,2,4-triazolo[4,3-b]pyridazinyl.

The preferred nonaromatic heterocyclic group includes oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,piperazinyl, pyrrolidino, piperidino, and morpholino.

The halogen includes fluorine, chlorine, bromide, and iodine, and ispreferably fluorine or chlorine.

The amino group that may be substituted includes amino (--NH₂) that maybe mono- or di-substituted by, for example, C₁₋₁₀ alkyl groups, C₃₋₁₀cycloalkyl groups, C₂₋₁₀ alkenyl groups, C₃₋₁₀ cycloalkenyl groups,C₁₋₁₃ acyl groups (e.g. C₂₋₁₀ alkanoyl groups, C₇₋₁₃ arylcarbonylgroups), or C₆₋₁₂ aromatic groups. As examples of the substituted aminogroup, there can be mentioned methylamino, dimethylamino, ethylamino,diethylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino,propionylamino, benzoylamino, phenylamino, and N-methyl-N-phenylamino.

The acyl group in the acyl groups that may be substituted includes C₁₋₁₃acyl groups. For example, formyl and groups formed between carbonyl andC₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₂aryl, or aromatic heterocyclic groups (e.g. thienyl, furyl, pyridyl).The preferred acyl group includes acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl. The substitutent in thesubstituted acyl groups includes C₁₋₃ alkyl, C₁₋₃ alkoxy groups, halogen(e.g. chlorine, fluorine, bromine, etc.), nitro, hydroxy, and amino.

Referring to the hydroxy group that may be substituted, the substitutedhydroxy includes alkoxy, alkenyloxy, aralkyloxy, acyloxy, and aryloxygroups.

The preferred alkoxy group includes C₁₋₁₀ alkoxy groups, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy,nonyloxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.

The preferred alkenyloxy group includes C₂₋₁₀ alkenyloxy groups, such asallyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy,2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy.

The preferred aralkyloxy group includes C₇₋₁₀ aralkyloxy groups, such asphenyl-C₁₋₄ alkyloxy (e.g. benzyloxy, phenethyloxy, etc.).

The preferred acyloxy group includes C₂₋₁₃ acyloxy groups, morepreferably C₂₋₄ alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy,isobutyryloxy, etc.).

The preferred aryloxy group includes C₆₋₁₄ aryloxy groups, such asphenoxy, and naphthyloxy. This aryloxy group may have 1 or 2substituents such as halogen (e.g. chlorine, fluorine, bromine, etc.).The substituted aryloxy group includes 4-chlorophenoxy.

Referring to the thiol group that may be substituted, the substitutedthiol group includes alkylthio, cycloalkylthio, aralkylthio, andacylthio groups.

The preferred alkylthio group includes C₁₋₁₀ alkylthio groups, such asmethylthio, ethylthio, propylthios, isopropylthio, butylthio,isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio,neopentylthio, hexylthio, heptylthio, and nonylthio. The preferredcycloalkylthio group includes C₃₋₁₀ cycloalkylthio groups such ascyclobutylthio, cyclopentylthio, and cyclohexylthio.

The preferred aralkylthio group includes C₇₋₁₀ aralkylthio groups, suchas phenyl-C₁₋₄ alkylthio (e.g. benzylthio, phenethylthio, etc.).

The acylthio group is preferably a C₂₋₁₃ acylthio group, more preferablya C₂₋₄ alkanoylthio group (e.g. acetylthio, propionylthio, butyrylthio,isobutyrylthio, etc.).

The carboxyl group that may be esterified includes alkoxycarbonyl,aralkyloxycarbonyl, and aryloxycarbonyl groups.

The preferred alkoxycarbonyl group includes C₂₋₅ alkoxycarbonyl groups,such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, andbutoxycarbonyl.

The preferred aralkyloxycarbonyl group includes C₈₋₁₀ aralkyloxycarbonylgroups, such as benzyloxycarbonyl.

The preferred aryloxycarbonyl group includes C₇₋₁₅ aryloxycarbonylgroups, such as phenoxycarbonyl, and p-tolyloxycarbonyl.

The preferred substituent on the hydrocarbon or heterocyclic group for Rincludes C₁₋₁₀ alkyl groups, aromatic heterocyclic groups, and C₆₋₁₄aryl groups. Particularly preferred is C₁₋₃ alkyl, furyl, thienyl,phenyl, or naphthyl.

Referring to the formula (I), when the substituent on the hydrocarbon orheterocyclic group for R is an alicyclic hydrocarbon group, an arylgroup, an aromatic heterocyclic group, or a nonaromatic heterocyclicgroup, this substituent may be further substituted by one or more,preferably 1 to 3 suitable substituents. As such substituents, there canbe mentioned C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₂₋₆ alkynylgroups, C₃₋₇ cycloalkyl groups, C6-14 aryl groups (e.g. phenyl,naphthyl, etc.), aromatic heterocyclic groups (e.g. thienyl, furyl,pyridyl, oxazolyl, thiaizolyl, etc.), nonaromatic heterocyclic groups(e.g. tetrahydrofuryl, morpholino, thiomorpholino, piperidino,pyrrolidino, piperazino, etc.), C₇₋₉ aralkyl groups, amino,N-mono(C₁₋₄)alkylamino groups, N,N-di(C₁₋₄)alkylamino groups, C₂₋₈acylamino groups (e.g. acetylamino, propionylamino, benzoylamino, etc.),amidino, C₂₋₈ acyl groups (e.g. C₂₋₈ alkanoyl groups, etc.), carbamoyl,N-mono(C₁₋₄ )alkylcarbamoyl groups, N,N-di(C₁₋₄)alkylcarbamoyl groups,sulfamoyl, N-mono(C₁₋₄)alkylsulfamoyl groups, N,N-di(C₁₋₄)alkylsulfamoylgroups, carboxyl, C₂₋₈ alkoxycarbonyl groups, hydroxy, C₁₋₄ alkoxygroups, C₂₋₅ alkenyloxy groups, C₃₋₇ cycloalkyloxy groups, C₇₋₉aralkyloxy groups, C₆₋₁₄ aryloxy groups (e.g. phenyloxy, naphthyloxy,etc.), mercapto, C₁₋₄ alkylthio groups, C₇₋₉ aralkylthio groups, C₆₋₁₄arylthio groups (e.g. phenylthio, naphthylthio, etc.), sulfo, cyano,azido, nitro, nitroso, and halogen (e.g. fluorine, chlorine, bromine,iodine).

In the formula (I), R is preferably a heterocyclic group that may besubstituted. More preferably, R is pyridyl, oxazolyl, or thiazolylgroup, which may have 1 to 3 substituents selected from C₁₋₃ alkyl,furyl, thienyl, phenyl, and naphthyl.

Referring to the formula (I), Y represents --CO--, --CH(OH)--, or --NR³--. Y is preferably --CH(OH)-- or --NR³ -- and more preferably--CH(OH)--. Referring to an alkyl group that may be substituted for R³,the alkyl group includes C₁₋₄ alkyl groups, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl. Thesubstituent includes halogen (e.g. fluorine, chlorine, bromine, iodine),C₁₋₄ alkoxy groups (e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy,sec-butoxy, t-butoxy), hydroxy, nitro, and C₁₋₄ acyl groups (e.g formyl,acetyl, propionyl, etc.).

The symbol n represents 0, 1 or 2 and is preferably 0 or 1.

The symbol X represents CH or N and is preferably CH.

Referring to the formula (I), A represents a bond or a bivalentaliphatic hydrocarbon group having 1 to 7 carbon atoms. This aliphatichydrocarbon group may be straight-chain or branched and may further besaturated or unsaturated. Thus, for example, --CH₂ --, --CH(CH₃)--,--(CH₂)₂ --, --CH(C₂ H₅)--, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ --,--(CH₂)₆ --, --(CH₂)₇ --, etc. can be mentioned for the saturatedbivalent aliphatic hydrocarbon group, while --CH═CH--, --C(CH₃)═CH--,--CH═CH--CH₂ --, --C(C₂ H₅)═CH--, --CH₂ --CH═CH--CH₂ --, --CH₂ --CH₂--CH═CH--CH₂ --, --CH═CH--CH═CH--CH₂ --, --CH═CH--CH═CH--CH═CH--CH₂ --,etc. can be mentioned for the unsaturated bivalent aliphatic hydrocarbongroup. The symbol A preferably represents a bond or a bivalent aliphatichydrocarbon group having 1 to 4 carbon atoms, which is preferably asaturated group. More preferably, A represents a bond, --CH₂ --or--(CH₂)₂ --. Still more preferably, A represents a bond or --(CH₂)₂ --.

The alkyl group for R¹ includes C₁₋₄ alkyl groups such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl. Preferably,R¹ represents hydrogen.

Referring to the formula (I), the partial structural formula: ##STR3##wherein each symbols has the same meanings as defined above.

Furthermore, ring E may optionally have 1 to 4 substituents atsubstitutable positions. Such substituents include an alkyl group, ahydroxy group that may be substituted, halogen, an acyl group that maybe substituted, nitro, and an amino group that may be substituted. Thesesubstituents may be the same as the substituents mentioned for thehydrocarbon or heterocyclic group for R.

Ring E, the partial structural formula: ##STR4## wherein R² representshydrogen, an alkyl group, a hydroxy group that may be substituted,halogen, an acyl group that may be substituted, nitro, or an amino groupthat may be substituted.

The alkyl group, hydroxy group that may be substituted, halogen, acylgroup that may be substituted, and amino group that may be substituted,for R² , may each be the same as that mentioned for the hydrocarbon orheterocyclic group for R. Preferably, R² is hydrogen, hydroxy group thatmay be substituted, or halogen. More preferably, R² is hydrogen orhydroxy group that may be substituted. Particularly preferred ishydrogen or a C₁₋₄ alkoxy group.

L and M respectively represent hydrogen or may be combined with eachother to form a bond, and preferably they are hydrogen.

Referring to the formula (I), the compound in which L and M are combinedwith each other to form a bond: ##STR5## wherein each symbols has thesame meanings as defined above, may exist as (E)- and (Z)-isomers, owingto the double bond at 5-position of the azolidinedione ring.

The compound in which L and M respectively represent hydrogen: ##STR6##wherein each symbols has the meanings as defined above, may exist asoptical isomers, i.e. (R)- and (S)-forms, with respect to the asymmetriccarbon at 5-position of the azolidinedione ring. This compound includesthose optically active compounds, i.e. (R)- and (S)-forms, as well asthe racemic form.

Referring to the formula (I) of the present invention, when m and n are0; X represents CH; A represents a bond; Q represents sulfur; R¹, L, andM respectively represent hydrogen; and ring E does not have furthersubstituents, R is not dihydrobenzopyranyl.

The preferred compound of the formula (I) is the compound in which Rrepresents pyridyl, oxazolyl, or thiazolyl group, optionally having 1 to3 substituents selected from the group consisting of C₁₋₃ alkyl, furyl,thienyl, phenyl, and naphthyl; Y represents --CH(OH)--; n is 0 or 1; Xrepresents CH; A represents a bond or --(CH₂)₂ --; R¹ representshydrogen; ring E, namely the partial structural formula: ##STR7## R² ishydrogen or a C₁₋₄ alkoxy group; and L and M respectively representhydrogen.

As preferred species of the compound of the formula (I), the followingcompounds (1) to (7) are mentioned.

(1) 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione,

(2)5-[4-[2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione,

(3)(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione,

(4)(S)-(-)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione,

(5)5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)phenyl]propyl]-2,4-oxazolidinedione,

(6)5-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)phenyl]pentyl]-2,4-oxazolidinedione,

(7)5-[3-[3,5-dimethoxy-4-[2-[(E)-styryl]-4-oxazolyl-methoxy]phenyl]propyl]-2,4-oxazolidinedione(hereafter, these compounds are sometimes simply referred to as compound(1), compound (2), and the like).

Among the above compounds, compounds (1) to (3), (5), and (6) arepreferred, and compounds (1) to (3) are particularly preferred.

The salt of compound (I) of the present invention is preferably apharmacologically acceptable salt, which includes salts with inorganicbases, salts with organic bases, salts with inorganic acids, salts withorganic acids, and salts with basic or acidic amino acids.

The preferred salt with an inorganic base includes alkali metal saltssuch as sodium salt, potassium salt, etc.; alkaline earth metal saltssuch as calcium salt, magnesium salt, etc.; aluminum salt, and ammoniumsalts.

The preferred salt with an organic base includes salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N'-dibenzylethylenediamine, etc.

The preferred salt with an inorganic acid includes salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc.

The preferred salt with an organic acid includes salts with formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

The preferred salt with a basic amino acid includes salts with arginine,lysine, ornithine, etc. The preferred salt with an acidic amino acidincludes salts with aspartic acid, glutamic acid, etc.

The most preferred of all the above-mentioned salts is sodium salt orpotassium salt.

Compound (I) or a salt thereof of the present invention can be producedin accordance with methods described in JP-A S55(1980)-22636(EP-A-8203), JP-A S60(1985)-208980 (EP-A-155845), JP-A S61(1986)-286376(EP-A-208420), JP-A S61(1986)-085372 (EP-A-177353), JP-AS61(1986)-267580 (EP-A-193256), JP-A H5(1993)-86057 (WO-A-9218501), JP-AH7(1995)-82269 (EP-A-605228), JP-A H7(1995)-101945 (EP-A-612743),EP-A-643050, EP-A-710659 (JP Application H7(1995)-284106), etc, ormethods analogous thereto.

Compound (I) or a salt thereof of the present invention (hereinafterreferred to as compound of the present invention) have anticachecticactivity, that is the activity to relieve the systemic syndromefeaturing progressive loss of body weight (inclusive of weight loss dueto lipolysis and weight loss due to myolysis), anemia, edema, andanorexia in chronic diseases such as malignant tumor, tuberculosis,diabetes, blood dyscrasia, endocrine disease, infectious disease, andacquired immunodeficiency syndrome. In addition, the toxic potential ofthe compound of the present invention is low.

The composition for prophylaxis and treatment of the present inventioncan be used as an agent for prophylaxis and treatment of cachexia or anagent for treatment of malnutrition in mammals (e.g man, mouse, rat,rabbit, dog, cat, bovine, equine, swine, monkey, etc.).

The cachexia is, for example, cancer cachexia, tuberculous cachexia,diabetic cachexia, hemodyscrasia-related cachexia, endocrinedisease-associated cachexia, infectious disease-associated cachexia, oracquired immunodeficiency syndrome-associated cachexia.

The composition for prophylaxis and treatment of the present inventioncan be used preferably in cachexia associated with malignant tumor,especially a carcinoma.

The composition for prophylaxis and treatment of the present inventionincludes the compound of the invention as such. Usually, the compositionis provided in a pharmaceutical dosage form by formulating the compoundof the invention with per se known pharmaceutically acceptable carriers.

As the pharmaceutically acceptable carrier a variety of organic andinorganic carriers in common use as raw materials for pharmaceuticalpreparations are employed. Thus, the carrier includes the excipient,lubricant, binder, and disintegrator for a solid dosage form; and thesolvent, solubilizer, suspending agent, isotonizing agent, bufferingagent and local analgesic for a liquid dosage form. Where necessary,pharmaceutical additives such as the preservative, antioxidant, coloringagent, sweetener, etc. can also be used.

The preferred excipient includes lactose, sucrose, D-mannitol, starch,crystalline cellulose, light silicic anhydride, etc.

The preferred lubricant includes magnesium stearate, calcium stearate,talc, colloidal silica, etc.

The preferred binder includes crystalline cellulose, sucrose,D-mannitol, trehalose, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.

The preferred disintegrator includes starch, carboxymethylcellulose,carboxymethylcellulose calcium, croscarmellose sodium,carboxymethylstarch sodium, etc.

The preferred solvent includes water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, tricaprylin, etc.

The preferred solubilizer includes polyethylene glycol, propyleneglycol, D-mannitol, trehalose, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, etc.

The preferred suspending agent includes surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate, etc. and hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylcellulose.

The preferred isotonizing agent includes sodium chloride, glycerin,D-mannitol, etc.

The preferred buffering agent includes buffer solutions such asphosphate, acetate, carbonate, citrate.

The preferred local anesthetic includes benzyl alcohol.

The preferred antiseptic includes p-hydroxybenzoic esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid, etc.

The preferred antioxidant includes salts of sulfurous acid, ascorbicacid, etc.

The above medicinal composition can be manufactured by the establishedpharmaceutical procedures, for example the procedures described in theJapanese Pharmacopoeia.

The medicinal composition can be provided in a variety of dosage forms,e.g. oral dosage forms such as tablets, capsules (inclusive of softcapsules and microcapsules), powders, granules, and syrups; and non-oraldosage forms such as injections, suppositories, pellets, and dripinfusions. These dosage forms can be safely administered either orallyor non-orally.

The dosage of the composition for prophylaxis and treatment of thepresent invention differs depending on the subject, route ofadministration, clinical condition, etc. For oral administration to anadult patient with cachexia, for instance, the usual unit dose is about0.1 mg/kg to about 30 mg/kg, preferably about 2 mg/kg to about 20 mg/kg,as the compound of the invention which is an active ingredient, whichdose is preferably administered once to 3 times a day.

The composition for prophylaxis and treatment of the present inventioncan be administered together with other drugs such as chemotherapeuticagents and immunotherapeutic agents to the same subject, eitherconcurrently or at staggered times. The dosage of these drugs can beappropriately selected by referring to the respective recommendedclinical dose ranges. The mixing ratio of the composition forprophylaxis and treatment of the present invention and other drugs canbe appropriately selected according to the subject, age and body weightof the subject, current clinical status, administration time, dosageform, method of administration, and combination of drugs, among otherfactors.

The preferred chemotherapeutic agent includes alkylating agents (e.g.cyclophosphamide, ifosfamide), antimetabolites (e.g. methotrexate,5-fluorouracil), antitumor antibiotics (e.g. mitomycin, adriamycin),antitumor plant alkaloids (e.g. vincristine, vindesine, Taxol),cisplastin, carboplatin, and etoposide. Particularly preferred areFlutron and Neo-Flutron, which are 5-fluorouracil derivatives.

The preferred immunotherapeutic agent includes fungal or bacterial cellwall components (e.g. muramyl dipeptide derivatives, picibanil),immunostimulant polysaccharides (e.g. lentinan, schizophyllan, Krestin),recombinant cytokines (e.g. interferons, interleukins (IL)), and colonystimulating factors (e.g. granulocyte colony stimulating factor,erythropoietin). Particularly preferred are IL-1, IL-2, and IL-12.

Furthermore, drugs which are documented as being anticachectic in ananimal model or clinically, such as cyclooxygenase inhibitors (e.g.indomethacin) [Cancer Research, 49, 5935-5939, (1989)], progesteronederivatives (e.g. megestrol acetate) [Journal of Clinical Oncology, 12,213-225, 1994], glucocorticoids (e.g. dexamethasone), metoclopramides,tetrahydrocannabinols (the same literature as above), lipid metabolismimproving agents (e.g. eicosapentanoic acid) [British Journal of Cancer,68, 314-318, 1993], growth hormone, IGF-1, and antibodies to thecachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M may also beused together with the composition for prophylaxis and treatment of thepresent invention.

The compound of the present invention can be used in combination withdiuretic. In this case, the administration time of the compound of thepresent invention and diuretic are not limited, and they can beadministered to the same subject, either concurrently or at staggeredtimes. The dosage of the diuretic can be appropriately selected byreferring to the recommended clinical dose ranges. The mixing ratio ofthe compound of the present invention and diuretic can be appropriatelyselected according to the subject, age and body weight of the subject,current clinical status, administration time, dosage form, method ofadministration, and combination, among other factors. For example, whenthe subject is man, diuretic is used in a proportion of usually about0.01 to about 100 weight parts, preferably about 0.1 to about 20 weightparts, relative to one weight part of the compound of the presentinvention.

The diuretic includes xanthine derivative preparations (e.g. theobromineand sodium salicylate, theobromine and calcium salicylate), thiazidepreparations (e.g. ethiazide, cyclopenthiazide, trichlormethiazide,hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide,penflutizide, polythiazide, methyclothiazide), antialdosteronepreparations (e.g. spironolactone, triamterene), carbonate dehydrataseinhibitors (e.g. acetazolamide) chlorbenzenesulfonamide preparations(e.g. chlorthalidone, mefruside, indapamide), azosemide, isosorbide,ethacrynic acid, piretanide, bumetanide, and furosemide.

Among the compound of the present invention, especially a compound whichhas a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atomsfor A in the formula (I) or a salt thereof, has an activity to preventand treat atherosclerosis, and an activity to regulate appetite and foodintake in disorders associated with under-eating, such as anorexianervosa, and disorders associated with over-eating, such as obesity andanorexia bulimia. Therefore, such a compound or a salt thereof can beused, as such or by providing in a pharmaceutic dosage form in the samemanner as described above, as an agent for prophylaxis and treatment ofatherosclerosis, or medicine for the regulation of appetite and foodintake.

The subject, dosage form, and dosage of the agent for prophylaxis andtreatment and the medicine are analogous to those in the case of theabove-described composition for prophylaxis and treatment of the presentinvention.

Among the compound of the present invention, a compound or a saltthereof which has a bivalent aliphatic hydrocarbon group having 1 to 7carbon atoms for A in the formula (I), has an activity to treat impairedglucose torelance, namely an activity to reduce fasting insulin levels,improve insulin sensitivity, and return glucose torelance to the normalrange. Based on such an activity, said compound or a salt thereof cantreat impaired glucose torelance in order to prevent or delay the onsetof noninsulin-dependent diabetes melitus. Such a compound or a saltthereof can be used, as such or by providing in a pharmaceutic dosageform in the same manner as described above, as a treating agent ofimpaired glucose torelance.

The subject, dosage form, and dosage of the treating agent are analogousto those in the case of the above-described composition for prophylaxisand treatment of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples and test examples are intended to describe thepresent invention in further detail and should by no means be construedas defining the scope of the invention.

EXAMPLE 1 Production of Capsules

    ______________________________________                                        1) Compound (2)         100    mg                                               2) Microcrystalline cellulose 30 mg                                           3) Lactose 37 mg                                                              4) Magnesium stearate 3 mg                                                    Total: 170 mg                                                               ______________________________________                                    

The above components 1), 2), 3) and 4) were mixed and filled in agelatin capsule.

EXAMPLE2 Production of Soft Capsules

    ______________________________________                                        1) Compound (2)       50     mg                                                 2) Corn oil 100 mg                                                            Total: 150 mg                                                               ______________________________________                                    

The components 1) and 2) were mixed and filled in a soft capsule in aconventional manner.

EXAMPLE 3 Production of Tablets

    ______________________________________                                        1) Compound (2)         100    mg                                               2) Lactose 34 mg                                                              3) Corn starch 10.6 mg                                                        4) Corn starch (paste) 5 mg                                                   5) Magnesium stearate 0.4 mg                                                  6) Carboxymethylcellulose calcium 20 mg                                       Total: 170 mg                                                               ______________________________________                                    

The above components 1) to 6) were mixed and compressed with a tabletingmachine in a conventional manner.

TEST EXAMPLE 1 Antilipolytic Activity

In accordance with the method of Green et al. [Endocrinology, 134,2581-2588 (1994)], the antilipolytic activity of the compound of thepresent invention was evaluated by quantitating the glycerol releasedfrom fat cells in rat epididymis adipose tissue.

Thus, the rat epididymis adipose tissue was isolated, cut into pieceswith a pair of scissors, and digested into fat cells by agitating incollagenase-containing phosphate buffer for 1 hour. To a culturesolution containing fat cells was added 10 ng/ml of IL-1β (manufacturedby Pharmingen, PM-19101V). Then, in treatment groups, solutions ofcompound (2) in N,N-dimethylformamide at graded concentrations wererespectively added. After 24 hours, the supernatant was recovered andthe glycerol therein was quantitated with an assay kit (manufactured bySigma, 337-A). The amount of released glycerol in each group treatedwith compound (2) relative to that in the control group was determinedto find the inhibition rate and the 50% inhibition concentration IC₅₀ ofthe compound was calculated. The antilipolytic concentration IC₅₀ valueof compound (2) was 4 nM.

TEST EXAMPLE 2 Weight Loss Inhibitory Activity in Tumor-Bearing Mice

Using the mouse colon cancer cell line Colon 26 (Tanaka et al., CancerResearch, 50, 4528-4532 (1990)), which is a system known to be high inthe reproducibility of cancer cachectic symptoms, the inhibitory effectof the compound of the present invention on lipolysis and body weightloss was evaluated.

Thus, 1×10⁶ Colon 26 cells were transplanted subdermaly in 4-week-oldCDF1 mice. On day 14 after transplantation, the mice were divided intogroups according to tumor size. A 5% (w/v) gum arabic suspensioncontaining compound (2) was administered orally in a dose of 1.0 mg/kgto one group of mice and, as a control, a 5% (w/v) gum arabic suspensionwas similarly administered to another group, once daily for 7 days ineach case. An additional group of mice was not transplanted with Colon26 cells (normal group). On days 14, 18 and 21 after transplantation,the mice were weighed. On day 22 after transplantation, each mouse wasautopsied and the epididymis adipose tissue was isolated and weighed.Changes in mouse body weight and adipose tissue weight are shown inTable 1 and Table 2, respectively.

                  TABLE 1                                                         ______________________________________                                        Changes in body weight (g) of tumor-bearing                                     mice                                                                                  14th Day after                                                                            18th Day after                                                                           21st Day after                                 transplantation transplantation transplantation                             ______________________________________                                        Normal group                                                                            28.3        29.4       29.4                                           Control group 25.4 23.3 21.3                                                  Medicated group 26.3 26.3 25.6                                              ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Adipose tissue weights (mg)                                                     of tumor-bearing mice                                                                      22nd Day after                                                   transplantation                                                             ______________________________________                                        Normal group   769                                                              Control group 74                                                              Medicated group 271                                                         ______________________________________                                    

It will be apparent from Tables 1 and 2 that the compound of the presentinvention suppresses lipolysis and weight loss which are cancercachectic symptoms due to transplantation of mouse colon cancer cellline Colon 26, indicating that it is useful as a treating agent forcachexia.

COMPARATIVE EXAMPLE

The antilipolytic activity of indomethacin was evaluated by the samemethod as in Test Example 1. The antilipolytic concentration IC₅₀ valueof indomethacin was not less than 10 mM.

INDUSTRIAL APPLICABILITY

The composition for prophylaxis and treatment of the present inventionis of value as an agent for prophylaxis and treatment of cachexia whichdevelops in chronic diseases such as malignant tumor, tuberculosis,diabetes, blood dyscrasia, endocrine disease, infectious disease, andacquired immunodeficiency syndrome. The composition for prophylaxis andtreatment of the present invention is conducive to relief of thesystemic syndrome, the cardinal signs of which are progressive loss ofbody weight (inclusive of weight loss due to lipolysis and weight lossdue to myolysis), anemia, edema, and anorexia, in said chronic diseases.

What is claimed is:
 1. A method for treating cachexia selected from thegroup consisting of cancer cachexia, tuberculous cachexia,hemodyscrasia-related cachexia, endocrine disease-associated cachexia,infectious disease-associated cachexia, and acquired immuno-deficiencysyndrome-associated cachexia in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundof the formula: ##STR8## wherein R represents a hydrocarbon group thatmay be substituted or a heterocyclic group that may be substituted; Yrepresents a group of the formula --CO--, --CH(OH)--, or --NR³ --wherein R³ represents an alkyl group that may be substituted; m is 0 or1; n is 0, 1 or 2; X represents CH or N; A represents a bond or abivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Qrepresents oxygen or sulfur; R¹ represents hydrogen or an alkyl group;ring E may have further 1 to 4 substituents, which may form a ring incombination with R¹ ; L and M respectively represent hydrogen or may becombined with each other to form a bond; provided that R does notrepresent dihydrobenzopyranyl when m and n are 0, X represents CH, Arepresents a bond, Q represents sulfur, R¹, L and M respectivelyrepresent hydrogen, and ring E does not have further substituents; or asalt thereof.
 2. The method according to claim 1, wherein theheterocyclic group represented by R is a 5- to 7-membered heterocyclicgroup containing 1 to 4 hetero-atoms selected from oxygen, sulfur, andnitrogen in addition to carbon as ring members or a condensed ringgroup.
 3. The method according to claim 1, wherein R represents aheterocyclic group that may be substituted.
 4. The method according toclaim 3, wherein the heterocyclic group is pyridyl, oxazolyl, orthiazolyl.
 5. The method according to claim 1, wherein the partialstructural formula: ##STR9##
 6. The method according to claim 1, whereinn is 0 or
 1. 7. The medicinal composition according to claim 1, whereinX represents CH.
 8. The method according to claim 1, wherein Arepresents a bond or a bivalent aliphatic hydrocarbon group having 1 to4 carbon atoms.
 9. The method according to claim 1, wherein R¹represents hydrogen.
 10. The method according to claim 1, wherein L andM respectively represent hydrogen.
 11. The method according to claim 1,wherein the compound is5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione,5-[4-[2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl-2,4-thiazolidinedione,5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione,5-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl=9-2,4-oxazolidinedione, or(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione.